KR20020069437A - 4-hydroxyphenylglycine anhydrides and process for the preparation thereof - Google Patents
4-hydroxyphenylglycine anhydrides and process for the preparation thereof Download PDFInfo
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
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Abstract
Description
본 발명은 경구용 세팔로스포린계 항생제의 제조시 중간체로 사용될 수 있는 신규 화합물인 하기 화학식 1의 4-히드록시페닐글리신 무수물(4-hydroxyphenylglycine anhydrides) 및 이의 제조방법에 관한 것이다.The present invention relates to 4-hydroxyphenylglycine anhydrides of the following general formula (1), which are novel compounds that can be used as intermediates in the preparation of oral cephalosporin-based antibiotics, and methods for their preparation.
화학식 1Formula 1
상기 식에서, R은 아미노 보호기를 의미한다.In the formula, R means amino protecting group.
경구용 세팔로스포린계 항생제인 세파트리진, 세파드록실 또는 세프프로질은 일반적으로 하기 화학식 2의 4-히드록시페닐글리신을 반응성 무수물로 전환시킨 다음 β-락탐핵의 아미노기와 아실화 반응시킴으로써 제조될 수 있다.The oral cephalosporin antibiotic cephatrizine, cephadoxyl or ceproprozil are generally converted to 4-hydroxyphenylglycine of formula 2 into reactive anhydride, followed by acylating the amino group of β-lactam nucleus. Can be prepared.
세팔로스포린계 항생제를 제조함에 있어서, 통상적으로 사용되는 반응성 무수물로는 산 염화물, 또는 머캅토벤조티아졸릴 에스테르, 포스포네이트 에스테르, 티오포스포네이트 에스테르 등과 같은 반응성 에스테르, 벤조트리아졸릴 아미드 같은 반응성 아미드, 이미다졸라이드, 트리아졸라이드 등과 같은 반응성 화합물 또는 혼합산 무수물 등이 있다. 그러나, 화학식 2의 4-히드록시페닐글리신 화합물의 경우에는 이의 4-위치 히드록시기가 카복실산기와 마찬가지로 친핵 반응성이어서 반응성 무수물로 제조하기가 매우 어렵다. 예를 들어, 활성 에스테르나 반응성 아미드의 경우 반응이 원하지 않는 부반응 쪽으로 진행되어 원하는 반응성 무수물을 순수한 상태로 분리 또는 수득할 수 없고, 이미다졸라이드 또는 트리아졸라이드의 경우에는 카복실산 외에 히드록시기에도 이미다졸라이드 또는 트리아졸라이드가 부가된 화합물이 수득되는 경향이 있어, 특히 이를 아실화 반응에 사용하면 R-, S- 라세미화(racemization)가 일어나는 문제점이 있다.In preparing cephalosporin antibiotics, reactive anhydrides commonly used include acid chlorides, or reactive esters such as mercaptobenzothiazolyl esters, phosphonate esters, thiophosphonate esters, and the like, benzotriazolyl amides. Reactive compounds such as amides, imidazolides, triazoles and the like or mixed acid anhydrides. However, in the case of the 4-hydroxyphenylglycine compound of the formula (2), its 4-positioned hydroxy group is nucleophilic reactive like the carboxylic acid group, making it very difficult to prepare a reactive anhydride. For example, in the case of active esters or reactive amides, the reaction proceeds towards undesired side reactions, whereby the desired reactive anhydride cannot be separated or obtained in the pure state, and in the case of imidazolides or triazides, they are also imides in hydroxyl groups in addition to carboxylic acids. There is a tendency for a compound to which a solide or triazide is added tends to be obtained, and in particular, when it is used in an acylation reaction, R- and S-racemization occurs.
한편, 산 염화물 반응성 무수물의 공지된 선행기술을 살펴보면, 미국 특허 제 3,925,418 호에는 4-히드록시페닐글리신을 포스겐과 반응시켜 N-카복시무수물을 제조하고 이에 염화수소 가스를 주입하여 최종적으로 산 염화물의 염산염 형태를 수득하는 방법이 제시되어 있는데, 이 방법에서는 매우 위험한 유독가스인 포스겐 및 염화수소 가스를 사용하므로 대량 반응시 안전성 측면에서 각별한 주의가 요구되며, 특히 독극물인 포스겐의 사용을 위해 별도의 장치나 설비가 요구된다는 어려움이 있을 뿐만 아니라 이의 사용 자체도 극히 제한적이라는 문제점이 있다.Meanwhile, referring to the known prior art of acid chloride reactive anhydride, U.S. Patent No. 3,925,418 discloses N-carboxy anhydride by reacting 4-hydroxyphenylglycine with phosgene to prepare N-carboxy anhydride and injecting hydrogen chloride gas into the hydrochloride salt of acid chloride. The method for obtaining the form is presented. In this method, very dangerous toxic gases such as phosgene and hydrogen chloride gas are used, so special care is required in terms of safety in a large amount of reactions, and in particular, a separate device or equipment for the use of the poison phosgene is used. Not only is there a difficulty in requiring it, but its use is extremely limited.
이에 본 발명자들은 전술한 공지의 반응성 유도체들이 갖는 문제점을 해결하기 위해 연구를 계속한 결과, 4-히드록시페닐글리신을 피발로일 할로겐화물과 반응시킴으로써, 경구용 세팔로스포린계 항생제의 제조에 유용하게 사용될 수 있는 신규한 화합물인 4-히드록시페닐글리신 무수물을 제조할 수 있게 되어 본 발명을 완성하게 되었다,Accordingly, the present inventors have continued research to solve the problems of the above-mentioned known reactive derivatives, and as a result, the reaction of 4-hydroxyphenylglycine with pivaloyl halide is useful in the preparation of oral cephalosporin antibiotics. It is possible to prepare 4-hydroxyphenylglycine anhydride, which is a novel compound that can be used easily.
본 발명의 목적은 경구용 세팔로스포린계 항생제의 제조시 중간체로서 사용될 수 있는 신규 화합물 및 이의 제조방법을 제공하는 것이다.It is an object of the present invention to provide novel compounds which can be used as intermediates in the preparation of oral cephalosporin antibiotics and methods for their preparation.
상기 목적에 따라 본 발명에서는 하기 화학식 1의 4-히드록시페닐글리신 무수물을 제공한다:According to the above object, the present invention provides 4-hydroxyphenylglycine anhydride of the following general formula:
화학식 1Formula 1
상기 식에서, R은 아미노 보호기를 의미한다.In the formula, R means amino protecting group.
또한, 본 발명에서는, 하기 화학식 3의 4-히드록시페닐글리신 화합물과 하기 화학식 4의 피발로일 할로겐화물을 염기 존재하에서 반응시키는 것을 포함하는, 화학식 1의 4-히드록시페닐글리신 무수물의 제조방법을 제공한다:In addition, in the present invention, a method for producing 4-hydroxyphenylglycine anhydride of formula (1) comprising reacting a 4-hydroxyphenylglycine compound of formula (3) with a pivaloyl halide of formula (4) in the presence of a base Provides:
상기 식에서, R은 상기에서 정의한 바와 같다.Wherein R is as defined above.
상기 식에서, X는 Cl, Br 또는 I를 의미한다.In the formula, X means Cl, Br or I.
이하 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명의 화학식 1의 4-히드록시페닐글리신 무수물 제조에 출발물질로 사용되는 화학식 3의 4-히드록시페닐글리신 화합물은 4-히드록시페닐글리신의 아미노기를 통상적인 보호그룹으로 보호함으로써 제조될 수 있다. 상기 통상적인 보호그룹이란 세팔로스포린계 화합물에서 관례적으로 사용되는 종류의 보호그룹을 의미하는 것으로, 기술적으로 잘 알려진 포밀, 아세틸, 클로로아세틸, 벤질, 벤질리덴, 살리실리덴, 디페닐메틸, 트리페닐메틸, 트리클로로에톡시카보닐, 테트라히드로피라닐, t-부톡시카보닐 또는 카보벤질옥시 등이 포함되며, 이 중 특히 산 처리에 의해 쉽게 제거될 수 있는 t-부톡시카보닐이 가장 바람직하다.The 4-hydroxyphenylglycine compound of formula 3 used as starting material for the preparation of 4-hydroxyphenylglycine anhydride of formula 1 of the present invention can be prepared by protecting the amino group of 4-hydroxyphenylglycine with conventional protecting groups. have. The conventional protecting group refers to a protecting group of a type conventionally used in cephalosporin-based compounds, and is well known formyl, acetyl, chloroacetyl, benzyl, benzylidene, salicylidene, diphenylmethyl, Triphenylmethyl, trichloroethoxycarbonyl, tetrahydropyranyl, t-butoxycarbonyl or carbenzyloxy, and the like, in particular t-butoxycarbonyl, which can be easily removed by acid treatment. Most preferred.
또한, 본 발명에 사용되는 화학식 4의 피발로일 할로겐화물은 통상적인 방법에 의해 제조하거나 상업적으로 용이하게 구입할 수 있다(문헌[Beil,2, 320]참조)In addition, the pivaloyl halide of formula (4) used in the present invention can be prepared by a conventional method or easily purchased commercially (see Beil , 2 , 320).
본 발명의 화학식 1의 4-히드록시페닐글리신 무수물은, 화학식 3의 4-히드록시페닐글리신 화합물과 화학식 4의 피발로일 할로겐화물 및 일정량의 염기를 적합한 용매에 혼합하여 반응시킴으로써 제조할 수 있다.4-hydroxyphenylglycine anhydride of the general formula (1) of the present invention can be prepared by mixing the 4-hydroxyphenylglycine compound of the general formula (3), pivaloyl halide of the general formula (4) and a predetermined amount of base in a suitable solvent .
이 때, 화학식 3의 4-히드록시페닐글리신 화합물 1.0 당량에 대한 화학식 4의 피발로일 할로겐화물의 양은 1.0 내지 2.0당량, 바람직하게는 1.1 내지 1.5당량이며, 적합한 용매로는 메틸렌 클로리드, 클로로포름, 사염화탄소, 아세토니트릴, 에틸 아세테이트, 디메틸포름아미드, 디메틸아세트아미드, 1,4-디옥산 및 테트라히드로퓨란으로 이루어진 군에서 선택된 하나 또는 2 이상의 혼합물이 있다. 용매의 사용량은 상기 화학식 3의 4-히드록시페닐글리신 화합물을 기준으로 3 내지 15 배(부피/중량), 바람직하게는 5 내지 10 배(부피/중량)이다.At this time, the amount of pivaloyl halide of Formula 4 to 1.0 equivalent of 4-hydroxyphenylglycine compound of Formula 3 is 1.0 to 2.0 equivalents, preferably 1.1 to 1.5 equivalents, and methylene chloride and chloroform are suitable solvents. , One or two or more mixtures selected from the group consisting of carbon tetrachloride, acetonitrile, ethyl acetate, dimethylformamide, dimethylacetamide, 1,4-dioxane and tetrahydrofuran. The amount of the solvent used is 3 to 15 times (volume / weight), preferably 5 to 10 times (volume / weight) based on the 4-hydroxyphenylglycine compound of Chemical Formula 3.
또한, 상기 반응에서 사용되는 염기로는 트리에틸아민, n-트리부틸아민, N,N-디메틸아닐린, 피리딘, N,N-디메틸아미노피리딘 등이 있으며, 이 중 트리에틸아민이 가장 바람직하다. 염기의 사용량은 상기 화학식 3의 4-히드록시페닐글리신 화합물 1.0 당량에 대하여 1.0 내지 1.5 당량, 바람직하게는 1.05 내지 1.2당량이다.In addition, bases used in the reaction include triethylamine, n-tributylamine, N, N-dimethylaniline, pyridine, N, N-dimethylaminopyridine and the like, of which triethylamine is most preferred. The use amount of base is 1.0 to 1.5 equivalents, preferably 1.05 to 1.2 equivalents based on 1.0 equivalent of 4-hydroxyphenylglycine compound of Chemical Formula 3.
본 발명의 방법에서 반응온도는 -10 내지 10℃, 특히 0 내지 5℃가 바람직하며, 반응 완결에 소요되는 시간은 반응온도, 염기의 종류 및 염기의 사용량에 따라 변할 수 있으나, 대략 1 내지 2 시간이면 충분하다.In the method of the present invention, the reaction temperature is preferably -10 to 10 ° C, in particular 0 to 5 ° C, and the time required for completion of the reaction may vary depending on the reaction temperature, the type of base, and the amount of base used. Time is enough.
본 발명에 따른 화학식 1의 4-히드록시페닐글리신 무수물은 새로운 구조의 혼합산 무수물로서, 통상의 시약을 사용하여 간단한 반응조건으로도 순수하게 수득할 수 있으며, 특히 β-락탐 핵의 아미노기와 아실화 반응시 R-, S- 라세미화가 전혀 일어나지 않고 부반응 없이 선택적으로 반응이 진행되므로, 결과적으로 세팔로스포린계 항생제인 세파트리진, 세파드록실 또는 세프프로질을 고순도 및 고수율로 수득하는데 유용하게 사용될 수 있다.4-hydroxyphenylglycine anhydride of the formula (1) according to the present invention is a mixed acid anhydride of a new structure, can be obtained purely even under simple reaction conditions using conventional reagents, in particular the amino group of the β-lactam nucleus During the misfire reaction, R- and S- racemization do not occur at all, and the reaction proceeds selectively without side reactions. As a result, the cephalosporin antibiotic cephatrizine, cephadroxyl or ceproprozil are obtained in high purity and high yield. It can be usefully used.
이하, 본 발명을 실시예에 의거하여 보다 상세하게 설명하고자 하나, 이는 본 발명의 구성 및 작용의 이해를 돕기 위한 것일 뿐이며 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, which are only intended to assist in understanding the configuration and operation of the present invention, and the scope of the present invention is not limited to these Examples.
제조예 : t-부톡시카보닐아미노-(4-히드록시페닐)아세트산(화학식 3의 화합물)의 제조Preparation Example: Preparation of t-butoxycarbonylamino- (4-hydroxyphenyl) acetic acid (compound of formula 3)
4-히드록시페닐글리신 33.4g(0.20몰)을 메탄올 340㎖에 섞은 후 트리에틸아민 41㎖(0.294몰)를 가한 다음, 약 40℃까지 승온시켰다. 이 때 현탁액이 점차 투명해지는데, 이 상태로 1 시간 동안 교반하였다. 이어서 온도를 상온으로 낮춘 다음 감압 증류하여 용매를 제거하고 에틸 아세테이트 400㎖ 및 물 100㎖를 가하였다. 5% HCl 용액으로 pH를 3.0 내외로 맞춘 다음 에틸 아세테이트 층을 분리한 후무수 황산 마그네슘으로 건조하였다. 이어서, 반응물을 여과하고 여액을 감압 증류하여 용매를 제거하고 잔사에 벤젠 200㎖를 가하여 30분간 교반하였다. 석출된 결정을 여과하고 벤젠으로 세척한 다음 진공 건조하여 백색의 목적 화합물 45.8g(수율:86%)을 수득하였다.33.4 g (0.20 mol) of 4-hydroxyphenylglycine was mixed in 340 ml of methanol, and 41 ml (0.294 mol) of triethylamine was added thereto, and the temperature was raised to about 40 ° C. At this time, the suspension gradually became transparent, but was stirred for 1 hour in this state. Subsequently, the temperature was lowered to room temperature, followed by distillation under reduced pressure to remove the solvent, and 400 ml of ethyl acetate and 100 ml of water were added thereto. The pH was adjusted to about 3.0 with 5% HCl solution, and then the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The reaction was then filtered, the filtrate was distilled under reduced pressure to remove the solvent, and 200 ml of benzene was added to the residue and stirred for 30 minutes. The precipitated crystals were filtered, washed with benzene and dried in vacuo to give 45.8 g (yield: 86%) of the white desired compound.
H-NMR(δ,DMSO-d6): 1.37(9H,s,-OC(CH3)3),4.94(1H,d,8.0Hz,-CH),6.69(2H,d,8.5Hz, 벤젠 환-H), 7.16(2H,d,8.5Hz, 벤젠 환-H), 9.42(1H,brs,NH), 12.57(1H,brs, COOH)H-NMR (δ, DMSO-d 6 ): 1.37 (9H, s, -OC (CH 3 ) 3 ), 4.94 (1H, d, 8.0 Hz, -CH), 6.69 (2H, d, 8.5 Hz, benzene Ring-H), 7.16 (2H, d, 8.5 Hz, benzene ring-H), 9.42 (1H, brs, NH), 12.57 (1H, brs, COOH)
실시예 1 : 피발로일 t-부톡시카르보닐아미노-(4-히드록시페닐)아세테이트의 제조Example 1 Preparation of Pivaloyl t-butoxycarbonylamino- (4-hydroxyphenyl) acetate
제조예에서 제조된 t-부톡시카르보닐아미노-(4-히드록시페닐)아세트산 26.7g(0.10몰)을 30㎖ 의 N,N-디메틸포름아미드와 100㎖ 의 메틸렌 클로리드의 혼합용매에 가하고 0℃ 까지 냉각시켰다. 이 반응액에 트리에틸아민 14.6㎖(0.105몰)를 가하고 10분 동안 교반한 후 피발로일 클로리드 12.9㎖(0.105몰)와 메틸렌 클로리드 70㎖ 를 혼합한 용액을 반응온도가 5℃ 이상 상승하지 않도록 주의하면서 20분 동안 점적하였다. 이어서, 0℃ 에서 30 분간 교반하고 유기층을 물로 100㎖ 씩 3회 세척하였다. 유기층을 무수 황산 마그네슘으로 건조시킨 후 여과하고 여액을 감압 증류한 다음, 진공 건조하여 백색 고체의 목적화합물 31.6g(수율:95%)을 수득하였다.26.7 g (0.10 mol) of t-butoxycarbonylamino- (4-hydroxyphenyl) acetic acid prepared in Preparation Example was added to a mixed solvent of 30 ml of N, N-dimethylformamide and 100 ml of methylene chloride. Cool to 0 ° C. 14.6 ml (0.105 mol) of triethylamine was added to the reaction solution, and the resultant was stirred for 10 minutes. Then, the reaction temperature was increased by 5 ° C. or more in a solution obtained by mixing 12.9 ml (0.105 mol) of pivaloyl chloride and 70 ml of methylene chloride. The drops were added for 20 minutes, taking care not to. Then, the mixture was stirred at 0 ° C. for 30 minutes and the organic layer was washed three times with 100 ml each time with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was distilled under reduced pressure, followed by vacuum drying to give 31.6 g (yield: 95%) of the title compound as a white solid.
H-NMR(δ, DMSO-d6) : 1.08(9H,s,피발로일 C(CH3)3),1.38(9H,s,-OC(CH3)3),5.20(1H, d,7.5Hz,-CH),6.74(2H,d,8.5Hz,벤젠 환-H),7.24(2H,d,8.5Hz, 벤젠 환-H),7.86(1H, d,7.4Hz,-NH),9.56(1H,s, -OH)H-NMR (δ, DMSO-d 6 ): 1.08 (9H, s, pivaloyl C (CH 3 ) 3 ), 1.38 (9H, s, -OC (CH 3 ) 3 ), 5.20 (1H, d, 7.5 Hz, -CH), 6.74 (2H, d, 8.5 Hz, benzene ring-H), 7.24 (2H, d, 8.5 Hz, benzene ring-H), 7.86 (1H, d, 7.4 Hz, -NH), 9.56 (1H, s, -OH)
IR(Cm-1,KBr) : 3451,2980,1804,1701,1513,1173,1055,1021,953.566IR (Cm -1 , KBr): 3451,2980,1804,1701,1513,1173,1055,1021,953.566
실시예 2: p-메톡시벤질 7β-[D-2-(t-부톡시카보닐아미노)-2-(p-히드록시페닐) 아세트아미도]-3-[프로펜-1-일]-3-세펨-4-카르복실레이트의 제조(세팔로스포린 항생제의 제조예)Example 2: p-methoxybenzyl 7β- [D-2- (t-butoxycarbonylamino) -2- (p-hydroxyphenyl) acetamido] -3- [propen-1-yl] Preparation of 3-Cefe-4-carboxylate (Preparation of Cephalosporin Antibiotic)
p-메톡시벤질 7-아미노-3-[프로펜-1-일]-3-세펨-4-카복실레이트 염산염 2.0g(5.04밀리몰)을 에틸 아세테이트 40㎖와 물 40㎖에 용해시키고 포화중조 용액을 가해 pH를 3.3에 맞추었다. 유기층을 분리하고 무수 마그네슘으로 건조한 후 다시 감압 증류하였다. 오일 상태의 잔사에 아세토니트릴 40㎖를 가하고 실시예 1에서 제조된 피발로일 t-부톡시카르보닐아미노-(4-히드록시페닐)아세테이트 1.77g(5.04밀리몰)을 혼합한 다음 상온에서 4시간 동안 교반하였다. 반응액을 감압 증류하여 아세토니트릴을 제거하고 에틸 아세테이트 40㎖와 물 40㎖를 가한 다음, 유기층을 분리하고 무수 황산 마그네슘으로 건조한 후 여과하고 여액을 다시 감압증류하였다. 잔사에 메탄올 10㎖를 가해 결정화하고 30분 동안 교반한 다음 석출된 결정을 여과하여 미백색의 목적화합물 2.82g(수율:89%)을 수득하였다.2.0 g (5.04 mmol) of p-methoxybenzyl 7-amino-3- [propen-1-yl] -3-cefe-4-carboxylate hydrochloride was dissolved in 40 ml of ethyl acetate and 40 ml of water, Was added to adjust the pH to 3.3. The organic layer was separated, dried over anhydrous magnesium, and then distilled under reduced pressure. 40 ml of acetonitrile was added to the oily residue, and 1.77 g (5.04 mmol) of pivaloyl t-butoxycarbonylamino- (4-hydroxyphenyl) acetate prepared in Example 1 was mixed, followed by 4 hours at room temperature. Was stirred. The reaction solution was distilled under reduced pressure to remove acetonitrile, 40 ml of ethyl acetate and 40 ml of water were added. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled under reduced pressure. 10 ml of methanol was added to the residue to crystallize, the mixture was stirred for 30 minutes, and the precipitated crystals were filtered to yield 2.82 g (yield: 89%) of the white target compound.
H-NMR(δ,DMSO-d6): 1.37(9H,s,-OC(CH3)3), 1.47(3Hx10/11,d,6.8Hz,Z-CH3), 1.74 (3Hx1/11,d,5.7Hz,E-CH3), 3.74(3H,s,-OCH3), 5.02~5.19(4H,m,-CO2CH2CH-,6-H), 5.53~5.60(1H,m,비닐H), 5.08~5.72(1H,m,7-H),6.01(1H,d,11.3Hz,비닐H), 6.65(2H,d,8.5Hz,벤젠 환-H), 6.91(2H,d,8.6Hz,벤젠 환-H), 7.19(2H ,d,8.5Hz,벤젠 환-H), 7.34(2H,d,8.6Hz,벤젠 환-H), 9.03(1H,d,8.4Hz-NH), 9.34(1H,s,-OH)H-NMR (δ, DMSO-d 6 ): 1.37 (9H, s, -OC (CH 3 ) 3 ), 1.47 (3Hx10 / 11, d, 6.8 Hz, Z- CH 3 ), 1.74 (3Hx1 / 11, d, 5.7 Hz, E -CH3), 3.74 (3H, s, -OCH 3 ), 5.02-5.19 (4H, m, -CO 2 CH 2 CH-, 6-H), 5.53-5.60 (1H, m, Vinyl H), 5.08 to 5.72 (1H, m, 7-H), 6.01 (1H, d, 11.3 Hz, vinyl H), 6.65 (2H, d, 8.5 Hz, benzene ring-H), 6.91 (2H, d , 8.6 Hz, benzene ring-H), 7.19 (2H, d, 8.5 Hz, benzene ring-H), 7.34 (2H, d, 8.6 Hz, benzene ring-H), 9.03 (1H, d, 8.4 Hz-NH ), 9.34 (1H, s, -OH)
본 발명에 따른 화학식 1의 4-히드록시페닐글리신 무수물은, 새로운 구조의 혼합산 무수물로서 통상의 시약을 사용하여 간단한 반응조건으로도 순수하게 수득할 수 있으며, 특히 β-락탐 핵의 아미노기와 아실화 반응시킬 때 R-, S- 라세미화가 전혀 일어나지 않고 부반응 없이 선택적으로 반응이 진행되므로, 결과적으로 세팔로스포린계 항생제인 세파트리진, 세파드록실 또는 세프프로질을 고순도 및 고수율로 수득하는데 유용하게 사용될 수 있다.4-hydroxyphenylglycine anhydride of the formula (1) according to the present invention can be obtained purely even under simple reaction conditions using conventional reagents as mixed acid anhydride of the new structure, especially amino group of β-lactam nucleus Since the reaction proceeds selectively without any R- and S-racemization and no side reactions, the cephalosporin antibiotics Sephatrizin, Sephadroxyl or Ceprozil are obtained in high purity and high yield. It can be useful to
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| US4148817A (en) * | 1976-03-25 | 1979-04-10 | Eli Lilly And Company | Process and intermediates for preparing cephalosporin antibiotics |
| US4203896A (en) * | 1976-12-23 | 1980-05-20 | Eli Lilly And Company | Acetoxy azetidin-2-one antibiotics via thiazolidine ring cleavage |
| US4144232A (en) * | 1976-12-23 | 1979-03-13 | Eli Lilly And Company | Substituted azetidin-2-one antibiotics |
| NL162387C (en) * | 1977-09-06 | 1980-05-16 | Gist Brocades Nv | PROCESS FOR PREPARING 6- (D-ALPHA-AMINO-P- HYDROXYPHENYLACETAMIDO) PENICILLANIC ACID. |
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